This invention relates generally to novel cyclic sulfonamide derivatives as metalloproteinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartillage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumsatnces including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-a from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also charactarized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechansisms are involved.
There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors.
WO95/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production. 
European Patent Application Publication No. 574,758 A1, discloses hydroxamic acid derivatives as collagenase inhibitors having the general formula:

GB 2 268 934 A and WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production.
The compounds of the current invention act as inhibitors of MMPs, in particular aggrecanase and TNF. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of aggrecanase, TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Accordingly, one object of the present invention is to provide novel cyclic sulfonamides which are useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, C, R1, R2, R3, and R4 are defined below, are effective metalloprotease inhibitors.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from COR5, xe2x80x94CO2H, CH(R)CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94CH(R)CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94NHRa, xe2x80x94N(OH)COR5, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94SONHRa, SN2H2Ra, PO(OH)2, and PO(OH)NHRa;
ring B is a 5-10 membered cyclic sulfonamide containing from 0-2 additional heteroatoms selected from O, NRb, and S(O)p, 0-1 carbonyl groups and 0-1 double bonds and ring B is substituted with 0-1 Rbxe2x80x2;
ring C is phenyl or a 5-6 membered heteroaromatic ring containing from 1-3 heteroatoms selected from O, N, NRa, and S(O)p, provided that when R3 or R4 contains a heteroatom bound to ring C, R3 or R4, respectively, is bound to other than a ring nitrogen;
R1 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x3NHQ, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)ORa, and (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)(CRRxe2x80x2)rNHC(O)ORa;
R, at each occurrence, is independently selected from H, CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3, and CH2CHxe2x95x90CH2;
Rxe2x80x2, at each occurrence, is independently selected from H, CH3, CH2CH3, and CH(CH3)2;
alternatively, R and Rxe2x80x2 together with the carbon to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group;
Q, at each occurence, is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R2 is selected from H, C1-10 alkylene-H, C2-10 alkenylene-H, C2-10 alkynylene-H, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94H, and (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94H;
R3 is Uxe2x80x94Xxe2x80x94Yxe2x80x94X1xe2x80x94Z;
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
X1 is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Y is absent or selected from O, NRa, S(O)p, S(O)pNRa, C(O)NRa, and C(O), provided that when U and Y are present, X is present;
Z is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rd and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
R4, at each occurence, is selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C3-6 carbocyclic residue, and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x3, at each occurrence, is independently selected from C1-4 alkyl, phenyl or benzyl;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb is selected from H, C1-6 alkyl, phenyl, benzyl, C(O)Ra, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, and S(O)pRaxe2x80x3;
Rbxe2x80x2 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x3NHQ, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)ORa, and (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)(CRRxe2x80x2)rNHC(O)ORa;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, xe2x80x94CH(xe2x95x90NOH), xe2x80x94C(xe2x95x90NOH)CH3, (CRRxe2x80x2)sO(CRRxe2x80x2)sxe2x80x2Rcxe2x80x2, (CRRxe2x80x2)sS(O)p(CRRxe2x80x2)sxe2x80x2Rcxe2x80x2, (CRRxe2x80x2)sNRa(CRRxe2x80x2)sxe2x80x2Rcxe2x80x2, C3-10 carbocyclic residue and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rcxe2x80x2, at each occurrence, is independently selected from phenyl substituted with 0-3 Rb, biphenyl substituted with 0-2 Rb, naphthyl substituted with 0-3 Rb and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, NRaC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5, at each occurrence, is selected from H, C1-10 alkyl substituted with 0-2 Re, and C1-8 alkyl substituted with 0-2 Rf;
Re, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, CF3, and CF2CF3;
Rf, at each occurrence, is selected from phenyl substituted with 0-2 Re and biphenyl substituted with 0-2 Re;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, xe2x80x94CH(R8)OC(xe2x95x90O)OR9, and 
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rg, C3-8 cycloalkyl substituted with 1-2 Rg, and phenyl substituted with 0-2 Re;
Rg, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, phenyl substituted with 0-2 Re;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
rxe2x80x2, at each occurrence, is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and,
s, at each occurrence, is selected from 0, 1, 2, and 3.
[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein;
A is selected from COR5, xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 6-8 membered cyclic sulfonamide containing from 0-2 additional heteroatoms selected from O, NRb, and S(O)p, and 0-1 carbonyl groups;
R1 is selected from H, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CH2)rxe2x80x2 O(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRa(CH2)rxe2x80x94Q, (CH2)rC(O)(CH2)rxe2x80x94Q, (CH2)rC(O)NRa(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRaC(O)(CH2)rxe2x80x94Q, (CH2)rxe2x80x2OC(O)NRa(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRaC(O)O(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRaC(O)NRa(CH2)rxe2x80x94Q, (CH2)rxe2x80x2S(O)p(CH2)rxe2x80x94Q, (CH2)rxe2x80x2SO2NRa(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRaSO2(CH2)rxe2x80x94Q, and (CH2)rxe2x80x2NRaSO2NRa(CH2)rxe2x80x94Q;
Q is selected from H, a C3-10 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R2 is selected from H, C1-6 alkylene-H, C2-6 alkenylene-H, C2-6 alkynylene-H, (CH2)rxe2x80x2O(CH2)rxe2x80x94H, (CH2)rxe2x80x2NRa(CH2)rxe2x80x94H, (CH2)rC(O)(CH2)rxe2x80x94H, (CH2)rC(O)NRa(CH2)rxe2x80x94H, (CH2)rxe2x80x2NRaC(O)(CH2)rxe2x80x94H, (CH2)rxe2x80x2SO2NRa(CH2)rxe2x80x94H, and (CH2)rxe2x80x2NRaSO2(CH2)rxe2x80x94H;
U is absent or is selected from: O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene;
X1 is absent or selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene;
Z is selected from H, a C5-10 carbocyclic residue substituted with 0-5 Rd and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
R4, at each occurrence, is selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C5-10 carbocyclic residue and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaxe2x80x2Ra, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; and,
rxe2x80x2, at each occurrence, is selected from 1, 2, 3, 4, and 5.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, and xe2x80x94N(OH)COR5;
ring B is a 6-8 membered cyclic sulfonamide containing from 0-1 additional heteroatoms selected from O, NRb, and S(O)p, and 0-1 carbonyl groups;
ring C is phenyl or a 5-6 membered heteroaromatic ring containing from 1-2 heteroatoms selected from O, N, NRa, and S(O)p, provided that when R3 or R4 contains a heteroatom bound to ring C, R3 or R4, respectively, is bound to other than a ring nitrogen;
Q is selected from H, a C5-10 carbocyclic residue substituted with 0-3 Rc and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rc;
R2 is selected from H, CH3, and CH2CH3;
U is absent or is selected from: O, NRa, C(O), C(O)NRa, NRaC(O), NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from C1-2 alkylene, C2-3 alkenylene, and C2-3 alkynylene;
X1 is absent or selected from C1-2 alkylene, C2-3 alkenylene, and C2-3 alkynylene;
Z is selected from H, a C5-6 carbocyclic residue substituted with 0-5 Rd and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd; and,
R4, at each occurrence, is selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S.
[4] In a further preferred embodiment, the present invention provides a novel compound of formula I, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, and xe2x80x94CONHOR5;
ring B is a 6-7 membered cyclic sulfonamide containing from 0-1 additional heteroatoms selected from NRb;
ring C is phenyl;
R1 is selected from H, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CH2)rxe2x80x2O(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRa(CH2)rxe2x80x94Q, (CH2)rC(O)(CH2)rxe2x80x94Q, (CH2)rC(O)NRa(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRaC(O)(CH2)rxe2x80x94Q, (CH2)rxe2x80x2OC(O)NRa(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRaC(O)O(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRaC(O)NRa(CH2)rxe2x80x94Q, (CH2)rxe2x80x2S(O)p(CH2)rxe2x80x94Q, (CH2)rxe2x80x2SO2NRa(CH2)rxe2x80x94Q, (CH2)rxe2x80x2NRaSO2(CH2)rxe2x80x94Q, and (CH2)rxe2x80x2NRaSO2NRa(CH2)rxe2x80x94Q;
Q is selected from H, a C5-6 carbocyclic residue substituted with 0-3 Rc and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rc;
R2 is H;
X is absent or selected from CH2 and CH2CH2;
X1 is absent;
Y is absent or selected from S(O)pNRa and C(O)NRa, provided that when U and Y are present, X is present;
Z is selected from H, phenyl substituted with 0-5 Rd and a 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C5-6 carbocyclic residue and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C3-6 carbocyclic residue and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; and,
s, at each occurrence, is selected from 0 and 1.
[5] In a further preferred embodiment, the present invention provides a novel compound of formula Ia; 
[6] In an even further preferred embodiment, the present invention provides novel compounds selected from:
4,5-dihydro-N-hydroxy-1,2,5-benzothiadiazepine-2(3H)-acetamide-1,1-dioxide;
4,5-dihydro-N-hydroxy-7-methoxy-1,2,5-benzothiadiazepine-2(3H)-acetamide-1,1-dioxide;
(R)-4,5-dihydro-N-hydroxy-alpha-methyl-1,2,5-benzothiadiazepine-2(3H)-acetamide-1,1-dioxide;
(R)-4,5-dihydro-N-hydroxy-7-methoxy-alpha-methyl-1,2,5-benzothiadiazepine-2(3H)-acetamide-1,1-dioxide;
(R)-4,5-dihydro-N-hydroxy-7-methoxy-alpha-(1-methylethyl)-1,2,5-benzothiadiazepine-2(3H)-acetamide-1,1-dioxide;
N-hydroxy-2(R)-[7-(3,5-dimethylbenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(3,5-dichlorobenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(3,5-dibromobenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(3,5-diethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(2,6-dichloropyridyl-4-methyleneoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(3-amino-5-methylbenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(3,5-dimethylbenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-3-methylbutanamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-3-methylbutanamide;
N-hydroxy-2(R)-[7-(3,5-diethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-3-methylbutanamide;
N-hydroxy-2(R)-[7-(4,5-dimethylthiazolyl-2-methyleneoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-3-methylbutanamide;
N-hydroxy-2(R)-[7-(3,5-dimethylbenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(3,5-dibromobenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(2-nitrophenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(2-aminophenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(2,6-dichloropyridyl-4-methyleneoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(pyridyl-4-methyleneoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(3,5-dichlorobenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(3,5-diethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methoxycarbonylbutanamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4 methoxycarbonylbutanamide;
N-hydroxy-2(R)-[7-amino-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentamide;
N-hydroxy-2(R)-[7-(N-acetylamino)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentamide;
N-hydroxy-2(R)-[7-(N-(2-phenylacetylamino)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentamide;
N-hydroxy-2(R)-[2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentamide;
N-hydroxy-2(R)-[7-(N-(3,5-dimethoxymethyleneamino)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentamide;
N-hydroxy-2(R)-[7-(N-(3,5-dimethylphenylmethyleneamino)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]propylamide;
N-hydroxy-2(R)-[7-(N-benzoylamino)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]propylamide;
N-hydroxy-2(R)-[7-(N-3,5-dimethoxybenzoylamino)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]propylamide;
N-hydroxy-2(R)-[7-(N-3,5-dimethylbenzoylamino)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]propylamide;
N-hydroxy-2(R)-[7-(phenylmethyleneoxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazeine-1,1-dioxide]-2-[(3,4,4-trimethyl-2,5-dioxa-1-imidazolidinyl)methyl]acetamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxyphenylmethyleneoxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]-2-[(3,4,4-trimethyl-2,5-dioxa-1-imidazolidinyl)methyl]acetamide;
N-hydroxy-2(R)-[7-(3,5-dimethylphenylmethyleneoxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]-2-[(3,4,4-trimethyl-2,5-dioxa-1-imidazolidinyl)methyl]acetamide;
N-hydroxy-2(R)-[7-(3,5-dibromophenylmethyleneoxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine-1,1-dioxide]-2-[(3,4,4-trimethyl-2,5-dioxa-1-imidazolidinyl)methyl]acetamide;
(R)-3,4-Dihydro-N-Hydroxy-alpha-(1-methylethyl)-2H-1,2-benzothiazine-2-acetamide-1,1-dioxide;
(R)-3,4-Dihydro-N-Hydroxy-alpha-2H-1,2-benzothiazine-2-acetamide-1,1-dioxide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-5-methoxycarbonylpentanamide;
N-hydroxy-2(R)-[7-(3,5-diethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-5-methoxycarbonylpentanamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-6-methoxycarbonylhexanamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-6-hydroxycarbonylhexanamide;
N-hydroxy-2(R)-[7-(4-nitrophenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(4-aminophenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(3-methyl-4-nitrophenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(2-nitrophenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(2-aminophenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-4-methylpentanamide;
N-hydroxy-2(R)-[7-(3-nitrophenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-phenoxy-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(4-methylthio-phenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(4-methoxyphenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(4-trifluoromethylphenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(4-methylsulfonylphenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(4-methoxycarbonylphenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(4-phenylphenoxy)-2,3,4,5-tetrahydrobenzo[1,2,5-f]thiadiazepine-1,1-dioxide]-propanamide;
N-hydroxy-2(R)-[7-(benzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-2-[(5,5-dimethyl-2,4-dioxa-3-oxazolidinyl)methyl]acetamide;
N-hydroxy-2(R)-[7-(benzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-3-N-(2-hydroxy-2-methylpropylamidyl)propylamide;
N-hydroxy-2(R)-[7-(benzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-[(1,1-dimethylethoxy)carbonyl]hexylamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-[(1,1-dimethylethoxy)carbonyl]hexylamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-amino-hexylamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-(acetamidyl)-hexylamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-(methanesulfonyl)-hexylamide;
N-hydroxy-2(R)-[7-(2,6-dimethoxypyridyl-4-methyleneoxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-[(1,1-dimethylethoxy)carbonyl]hexylamide;
N-hydroxy-2(R)-[7-(2,6-dimethoxypyridyl-4-methyleneoxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-aminohexylamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-(benzenesulfonyl)-hexylamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-(butylsulfonyl)-hexylamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-hexylamide;
N-hydroxy-2(R)-[7-(3,5-dimethoxybenzyloxy)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]-6-N-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-hexylamide;
N-hydroxy-2(R)-[7-phenyl-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]propylamide;
N-hydroxy-2(R)-[7-(2-trifluromethylphenyl)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]propylamide;
N-hydroxy-2(R)-[7-(phenylethynyl)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]propylamide; and,
N-hydroxy-2(R)-[7-(4-biphenylyl)-2,3,4,5-tetrahydro-benzo[1,2,5-f]thiadiazepine 1,1-dioxide]propylamide;
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel compound selected from the formulas: 
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-10 alkylxe2x80x9d or xe2x80x9cC1-10 alkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids,such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5xe2x80x2-triiodothyronine, and 3,3xe2x80x2,5,5xe2x80x2-tetraiodothyronine. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, 9-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated herein in their entirety by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A series of 2-substituted 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxides of formula 6 are prepared by the method outlined in Scheme 1. Reaction of a D-amino acid 1 with benzenesulfonyl chloride 2 provides sulfonamide 3. N-allylation with allyl bromide and sodium hydride followed by ozonolysis yields aldehyde 5. Reduction of nitro group and intramolecular reductive amination are achieved in one pot with zinc in acetic acid under reflux to provide 6. 
An alternative synthesis of the 2-substituted 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide series of formula 11 is outlined in Scheme 2. Standard coupling of D-amino acid 7 with 2 gives sulfonamide 8. The 2-bromoethyl group is then introduced to the sulfonamide via Mitsunobu coupling with 2-bromoethanol. Iron in acetic acid reduction of 9 gives aniline 10, which cyclizes to give the 2-substituted 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide upon treatment with N-methylmorpholine. 
Many of the requisite D-amino acid methyl esters 1 and tert-butyl esters 7 are commercially available or are prepared from commercial material by simple protecting group manipulations. Others are synthesized using Myers method from glycine (Myers, A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995, 117, 8488), using Mitsunobu conditions from serine (Cherney, R. J.; Wang, L. J. Org. Chem. 1996, 61, 2544), or using Evans electrophilic azidations from carboxylic acids (Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011).
Methyl ester 6 and tert-butyl ester 11 are converted to hydroxamic acid 14 following the route outlined in Scheme 3. Methyl ester hydrolysis with lithium hydroxide and tert-butyl ester hydrolysis with trifluoroacetic acid provide carboxylic acid 12. Coupling with O-benzyl hydroxylamine and reductive removal of benzyl group yield 14. Alternatively, treatment of methyl ester 6 with hydroxylamine and potassium hydroxide in methanol provides hydroxamic acid 14 in a single step. 
Compounds 6 from Scheme 1 and 11 from Scheme 2 are used as common intermediates for structure diversification. For example, when R3 is an amino group, 11 serves as common starting point for alkylated amine 15, amide 16, sulfonamide 17 and urea 18 (Scheme 4). 15-18 are converted to hydroxamic acids following the sequence outlined in Scheme 3. 
Some of the substituted (2-nitrobenzene)sulfonyl chlorides are commercially available. Others are prepared following known literature procedures. As an illustrated example, Scheme 5 outlines the synthesis of (4-benzyloxy-2-nitrobenzene)sulfonyl chloride (21). Selective protection of the hydroxy group with benzyl bromide and potassium tert-butoxide gives 20. Diazatization of 20 with sodium nitrite and treatment with sulfurous acid and cupric chloride provides the sulfonyl chloride 21. 
A series of 2-substituted 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxides of formula""s 23-26 are prepared by the method outlined in Scheme 6. When R3 is a benzyloxy group, compound 11 prepared from Scheme 2 is converted to phenol 22 by hydrogenolysis. Reaction of 22 with R5xe2x80x94X provides 23, an alternative is the reaction of 22 with R5xe2x80x94OH under Mitsunobu conditions to produce 23. R5 can be appended directly to the aromatic ring by converting 22 to an aryl triflate then reaction with an organometallic in the presence of a palladium (0) catalyst to give 24. 22 can also be reacted with acyl halides or isocyantes to afford 25. Biaryl ethers 26 can be produced by treatment of 22 with aryl boronic acids in the presence of a copper catalyst. 23-26 are then converted to the corresponding hydroxamic acids following the sequence outlined in Scheme 3. 
A series of 2,5-disubstituted 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxides of formulas 27-30 are prepared by the method outlined in Scheme 7. Compound 11 is converted to 27 by alkylation, amide 28 by acylation, sulfonamide 29 by sulfonylation, and urea 30 by reaction with isocyanate. 27-30 are then converted to the corresponding hydroxamic acid following the sequence outlined in Scheme 3. 
A series of 2-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides of formula 32 are prepared by the method outlined in Scheme 8. Reduction of 3 gives aniline 31. Treatment of 31 with formaldehyde under acidic conditions provides 32. 32 is then converted to the corresponding hydroxamic acid following the sequence outlined in Scheme 3. 
A series of 2-substituted 2,3-dihydro-1,2-benzisothiazole 1,1-dioxides of formula 37 are prepared by the method outlined in Scheme 9. Lithium aluminum hydride reduction of 33 gives benzisothiazole 34. Mitsunobu reaction with hydroxylester 35 or coupling with bromoester 36 under basic conditions provides 37. 37 is then converted to the corresponding hydroxamic acid following the sequence outlined in Scheme 3. 
A series of 2-substituted 3,4-dihydro-2H-1,2-benzothiazine 1,1-dioxides of formula 44 are prepared by the method outlined in Scheme 10. Following reduction of the nitro group, the resultant aniline is diazatized with sodium nitrite and treated with sulfur dioxide. Hydrolysis of sulfonyl chloride 40 and hydrogenation yield primary amine 42. Benzothiazine formation is accomplished with POCl3 followed by sodium hydroxide treatment. Mitsunobu reaction with hydroxylester 35 or coupling with bromoester 36 under basic conditions provides 44. 44 is then converted to the corresponding hydroxamic acid following the sequence outlined in Scheme 3. 
Alternatively, the 2-substituted 3,4-dihydro-2H-1,2-benzothiazine 1,1-dioxides of formula 44 are prepared by the method outlined in Scheme 11. Following protection of alcohol 45 with BnBr, lithium bromine exchange and reaction with sulfur dioxide provide the sulfonic acid lithium salt 46. Reaction of 46 with sulfuryl chloride and coupling with amine 1 yield sulfonamide 48. Cleavage of benzyl ether and intramolecular Mitsunobu reaction give 44. 44 is then converted to the corresponding hydroxamic acid following the sequence outlined in Scheme 3. 
A series of 2-substituted 2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxides of formula 56 are prepared by the method outlined in Scheme 12. Reaction of amine 7 with sulfonyl chloride 50 yields sulfonamide 51. Heck coupling with methyl acrylate gives 52. 52 is then converted to alcohol 55 by olefin reduction, methyl ester hydrolysis, and hydroboration of the resultant carboxylic acid. The formation of benzothiazepine 56 is accomplished by intramolecular Mitsunobu reaction on 55. 56 is then converted to the corresponding hydroxamic acid following the sequence outlined in Scheme 3. 
A series of 2-substituted 3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxides of formula 61 are prepared by the method outlined in Scheme 13. Coupling of amine 1 with sulfonyl chloride 57 gives sulfonamide 58. Mitsunobu reaction with 2-bromoethanol provides 59. Cleavage of benzyl ether and treatment with base such as cesium carbonate yield benzoxathiazepine 61. 61 is then converted to the corresponding hydroxamic acid following the sequence outlined in Scheme 3. 
A series of 2-substituted 3,4-dihydro-2H-4,1,2-benzoxathiazepine 1,1-dioxides of formula 63 are prepared by the method outlined in Scheme 14. Employing 58 as common intermediate, cleavage of benzyl ether and reaction with formaldehyde under acidic conditions yield benzoxathiazepine 63. 63 is then converted to the corresponding hydroxamic acid following the sequence outlined in Scheme 3. 
A series of 2,4-substituted 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxides of formula 67-70 are prepared by the method outlined in Scheme 15. The sequence is started with compound 8 from Scheme 2. The Mitsunobu reaction is performed with glycolaldehyde diethyl acetal to yield 64. Reduction is accomplished as before with iron to give 65. The cyclization is performed with pTsOH in warm DMF. The resulting compound 66 is a very versatile intermediate. A Grignard is added to 66 to give 67, which is converted to the hydroxamate as in Scheme 3. A nitrile is added to compound 66 through the use of TMSCN to afford 68. This is reduced to 69 and then substituted to 70. Compounds 68, 69 and 70 are converted to their respective hydroxamates via Scheme 3. 
One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).